MRI Biomarkers of Disease Progression in Inherited Neuropathies

遗传性神经病疾病进展的 MRI 生物标志物

• 批准号: 10756378
• 负责人: Richard Dortch
• 金额: $ 15.35万
• 依托单位: METHODIST HOSPITAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10756378
• 关键词: MRI; Biomarkers; Disease; Progression; Inherited

PROJECT SUMMARY The overarching goal of this proposal is to advance the clinical trial readiness of candidate magnetic resonance imaging (MRI) biomarkers of disease progression in Charcot-Marie-Tooth (CMT) disease type 1A (CMT1A), a dysmyelinating inherited neuropathy with secondary axonal loss. Although promising treatments for CMT1A are on the horizon, the evaluation of therapies in human trails is hindered by a lack of responsive biomarkers, which is critical due to the slowly progressive nature of CMT1A. The CMT neuropathy score (CMTNS) is a composite disability score proposed as a biomarker of CMT; however, the limited responsiveness of the CMTNS annually demands a formidably large sample size for use in CMT clinical studies. More recently, in- tramuscular fat percentage (via fat-water MRI) has been proposed as a more sensitive biomarker. Unfortunate- ly, fat replacement represents the chronic endpoint of CMT1A; therefore, it may be difficult to evaluate thera- pies that slow or halt (rather than reverse) progression in muscles that are already denervated using this measure. Based on our developed nerve MRI methods, we hypothesize that directly imaging the pathology of interest within nerves themselves may offer complementary information and improve our ability to monitor disease progression in patients with CMT1A. Published results from our labs indicate that sciatic nerve mag- netization transfer ratios (MTR), which are sensitive to myelin content changes from de/dysmyelination and axonal loss, relate to disability across CMT subtypes, and additional preliminary data indicate that nerve MTRs are responsive to disease progression. More recent preliminary and published data indicate that MRI- based nerve diameter estimates may be a specific biomarker of CMT1A. Together, these results indicate that nerve MRI may yield viable biomarkers of CMT; however, questions remain regarding: i) the relative respon- siveness of potential biomarkers based on nerve MRI (MTR and diameter) and muscle MRI (intramuscular fat); ii) the relationships between these candidate biomarkers and function (CMTNS, dynamometry), electrophysi- ology (nerve conduction studies, NCS), pathology (skin biopsy), and quality-of-life in the same cohort; and iii) whether imaging biomarkers of nerve/muscle yield reliable results across sites and vendors for use in future trials. We aim to address these gaps via the following aims: 1) determine the responsiveness of MRI-derived nerve MTR, nerve diameter, and intramuscular fat percentage values to disease progression in patients with CMT1A and 2) determine the inter-site and inter-vendor reproducibility and repeatability of nerve MTR, nerve diameter, and intramuscular fat percentage values. This proposal builds upon existing expertise of the teams at Wayne State and the Barrow Neurological Institute and is designed for each aim to be undertaken in parallel with coordinated effort across sites. If successful, these studies will provide responsive imaging biomarkers of CMT1A progression for future trials, which is critical due to the inverse relationship between responsiveness and the sample size needed to power clinical trials in this rare neurological disorder.

项目摘要 该提案的总体目标是提高候选磁共振的临床试验准备就绪 Charcot-Marie-Tooth（CMT）疾病1A型（CMT1A），A的成像（MRI）疾病进展的生物标志物 遗传性神经病伴有继发性轴突丧失。虽然有希望的CMT1A治疗 在范围内，由于缺乏反应敏感的生物标志物而阻碍了人类小径中疗法的评估， 由于CMT1A的渐进性缓慢，这至关重要。 CMT神经病评分（CMTN）是 提议作为CMT的生物标志物的综合残疾评分；但是，有限的响应能力 CMTN每年需要一个大量的样本量，以用于CMT临床研究。最近， 已经提出了施加敏感的生物标志物（通过脂肪 - 水MRI）。不幸- ly，脂肪替代代表CMT1A的慢性终点；因此，可能很难评估thera- 肌肉中已经被剥离的肌肉中缓慢或停止（而不是反向）进展的馅饼 措施。基于我们发达的神经MRI方法，我们假设直接成像 神经内部的兴趣可能会提供互补的信息，并提高我们监视的能力 CMT1A患者的疾病进展。我们实验室发表的结果表明，坐骨神经杂志 网络化转移比（MTR），对髓磷脂含量敏感，从DE/de障碍和 轴突丧失，与CMT亚型的残疾有关，其他初步数据表明神经 MTRS对疾病进展有反应。最新的初步和发布的数据表明，MRI- 基于基于的神经直径估计可能是CMT1A的特定生物标志物。这些结果一起表明 神经MRI可能会产生CMT的可行生物标志物；但是，关于：i）相对响应的问题仍然存在。 基于神经MRI（MTR和直径）和肌肉MRI（肌内脂肪）的潜在生物标志物的性能； ii）这些候选生物标志物与功能之间的关系（CMTN，动力学），电力学 同一队列中的OLOGOL（神经传导研究，NCS），病理学（皮肤活检）和生活质量；和iii） 是否成像神经/肌肉的生物标志物是否会在未来使用的站点和供应商中产生可靠的结果 试验。我们旨在通过以下目的解决这些差距：1）确定MRI衍生的响应能力 神经MTR，神经直径和肌肉内脂肪百分比值对患者的疾病进展 CMT1A和2）确定神经MTR，神经的位点间和供应商的可重复性和可重复性 直径和肌内脂肪百分比值。该提案以团队现有专业知识为基础 韦恩州立大学和巴罗神经学院，旨在平行进行每个目标 跨站点进行了协调的努力。如果成功，这些研究将提供响应式成像生物标志物 CMT1A的进展用于将来的试验，这是由于响应能力之间的反比关系至关重要 以及在这种罕见的神经系统疾病中为临床试验提供动力所需的样本量。